Solid phase dispersion of quinolone or naphthyridonecarboxylic acids

ABSTRACT

The present invention relates to a solid dispersion of quinolone- or naphthyridonecarboxylic acids in an insoluble matrix representative of a shellac, and methods preparing and using the same in masking the taste and improving the uptake by animals.

FIELD OF THE INVENTION

[0001] The present invention relates to the preparation of orallyadministrable formulations of quinolone- or naphthyridonecarboxylicacids and methods of making and using the same. More specifically, theinvention relates to quinolone- or naphthyridonecarboxylic acids in asolid phase dispersion, which masks their bitter taste.

BRIEF DESCRIPTION OF THE PRIOR ART

[0002] Quinolonecarboxylic acids and their formulations are alreadyknown. See, for example, EP-A (European Published Specification) 238814. Of particular interest here are formulations that are intended tomask the bitter taste of the active quinolone compounds. U.S. Pat. No.5,808,076 discloses a method of preparing an improved oral formulationof quinolone compounds by mixing the quinolones in the form of theiraqueous solution salts or derivatives with embonic acid. U.S. Pat. No.5,152,986 discloses a method of preparing and using ion exchange resinsloaded with quinolonecarboxylic acid derivatives.

[0003] It has now been found that orally administrable formulations ofquinolone- or naphthyridonecarboxylic acids can be obtained with solidphase dispersions of quinolone- or naphthyridonecarboxylic acids in aninsoluble matrix.

DESCRIPTION OF THE INVENTION

[0004] In accordance with the foregoing, the present inventionencompasses solid phase dispersion of an active ingredient of quinolone-or naphthyridonecarboxylic acid in an insoluble matrix in an effectiveamount to mask the taste of the active ingredient. Also encompassed bythe invention is a process for preparing the solid phase dispersion byadmixing quinolone- or naphthyridonecarboxylic acids with an insolublematrix to produce a solid dispersion. Preferably, the quinolone- ornaphthyridonecarboxylic acid is employed in a micronized form and morepreferably in the form of fine powder, and the insoluble matrix isemployed in the form of flakes or powder. In a presently preferredembodiment of the invention, these two components are first admixed bycomminuting them by say pulverizing micronized quinolone- ornaphthyridonecarboxylic acid with flakes of shellac. This is followed byfurther mixing and addition of water to form a hydrate, and by, say,melt mixing, and further comminuting to reduce particle size to providethe desired solid phase dispersion. By the term solid dispersion ismeant quinolone- or naphthyridonecarboxylic acid finely dividedparticles are distributed throughout the insoluble matrix.

[0005] It has surprisingly been found that the solid phase dispersion inaccordance with this invention provides greatly reduced quinolone- ornaphthyridonecarboxylic acid. particle size. It has also been found thatthe dispersion provides acceptable solubility of the quinolone- ornaphthyridonecarboxylic acid. It has also been found that the dispersionprovides controlled release of the quinolone- or naphthyridonecarboxylicacid, which can be administered orally without any problems even toanimals which will normally refuse formulations containing quinolone- ornaphthyridone-carboxylic acid owing to their bitter taste. Unexpectedly,the solid phase dispersion has an outstanding acceptance whenadministered.

[0006] Quinolone- or naphthyridonecarboxylic acids and derivatives areknown. See, for example, EP-A (European Published Specification) 350950, 302 372, 49 355, 47 005, 242 789, 259 804, 215 650, 131 839, 109284; DE-A (German Published Specification) 2 804 097; FR-P (FrenchPatent Specification) 2 463 771; PCT WO 92/9596. (The formulae and thespecific compounds mentioned in these publications are incorporatedherein by reference.)

[0007] Preferred compounds are temafloxacin, tosufloxacin, enrofloxacin,ciprofoxacin, ofloxacin, orbifloxacin, marbofloxacin, norfloxacin,benofloxacin, binfloxacin, danofloxacin, difloxacin, sarafloxacin,premafloxacin and ibafloxacin. Particularly preferred compounds are:enrofloxacin, danofloxacin and sarafloxacin. Derivatives of these activecompounds include their esters such as the C.sub.1-C.sub.4-alkyl esters.Salts of these active compounds include all salts with acids formingphysiologically acceptable salts. These include hydrohalic acids,sulfonic acids, carboxylic acids, amino acids, (poly)-hydroxycarboxylicacids, phosphonic acid, nitric acid and sulfuric acid. Specifically,these are methanesulfonic acid, ethanesulfonic acid,hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonicacid, formic acid, acetic acid, propionic acid, dimethylolpropionicacid, hydroxyacetic acid, lactic acid, hydroxymaleic acid, oxalic acid,succinic acid, fumaric acid, maleic acid, glutaric acid, malonic acid,adipic acid, ascorbic acid, malic acid, citric acid, tartaric acid,aminosalicyclic acid, anthranilic acid, benzoic acid, hydroxybenzoicacid, phenylacetic acid, salicylic acid, phthalic acid, nicotinic acid,mandelic acid, aspartic acid, glutamic acid, gluconic acid, glucuronicacid, latobionic acid, galaturonic acid, mucic acid, phosphoric acid,nitric acid, hydrochloric acid, sulfuric acid,5-oxotetrahydrofuran-2-carboxylic acid and 2-hydroxyglutaric acid.Particular preference is given to hydrochloric acid or gluconic acid.

[0008] Suitable bases for forming salts with quinolones ornaphthyridonecarboxylic acid are, for example, the following: alkalimetal and alkaline earth metal hydroxides, such as KOH, NaOH,Ca(OH).sub.2, ammonia, basic amino acids such as arginine, lysine,choline, N-methylglucamine, ethylenediamine, mono-, di-trialkylamines,substituted amines such as, for example, diethanolamine and cyclicamines such as, for example, morpholine, piperazine, tromethamol(=tris(hydroxymethyl)-aminomethane). Particularly suitable are KOH,arginine, lysine and N-methyl-glucamine.

[0009] The insoluble matrix can be characterized as a material in whichthe quinolone- or naphthyridonecarboxylic acid is so embedded that itmasks the taste of the quinolone- or naphthyridonecarboxylic acid andyet allows the same to be leached out and made pharmaceuticallyavailable to animals consuming the solid disperson. The quionolone- ornaphthyridonecarboxylic acid can be made available to the target speciesas it dissolves in say the intestinal fluid, and is absorbed into theblood stream. Illustrative but non-limiting examples of the insolublematrix can be selected from the group consisting of shellac, polyvinylalcohol, poly (D,L-lactic-co glycolic) acid, sugars, and polyethyleneglycol, which is preferably of high molecular weight. Preferred hereinis shellac, especially in form of flakes.

[0010] Suitable excipients, carriers and/or auxiliaries, which arepreferably organic or inorganic inert solid substances can be formulatedwith the solid phase dispersion. Inorganic and organic substances may beused in this capacity. Examples of inorganic substances are: commonsalt, carbonates (for example, calcium carbonic), hydrogencarbonates,aluminum oxides, silicas, clays, precipitated or colloidal silicondioxide and phosphates. Examples of organic substances are sugar andoptionally their derivatives, polyethylene glycols, paraffins, and fattyacids.

[0011] As a carrier, one can use a mixture of the substances mentionedin addition to cellulose and its derivatives, starches (for examplescorn, rice, potato, tapioca, or wheat starch), foodstuffs and feeds suchas, for example milk powder, animal meal, ground and bruised grain.Other carriers, which in addition have the property of binding water canbe employed. Example thereof are carboxymethyl cellulose, methylcellulose and other cellulose and starch derivatives, polyacrylates,alginates, gelatin, chitin, gum arabic, polyvinylpyrrolidone, polyvinylalcohols, copolymers of vinyl ether and acid anhydrides, polyethyleneglycols, waxes, colloidal silicas or mixtures of the substances andclasses of substances mentioned.

[0012] Auxiliaries such as preservatives, antioxidants,photostabilizers, colorants, absorption-promoting substances,disintegration-promoting substances, binders or lubricants andstabilizers may be used.

[0013] The method according to the invention comprises mixing theindividual components. Any convenient mixer, including high intensitymixers having chopping devices can be employed. The following is anon-limiting description of a method of preparation. The components canbe mixed together and passed through a cone-mill with a sieve size of1.0-8.0 mm at 500 to 800 rpm, to give a fine homogeneous powder.Illustratively, micronized quinolone- or naphthyridonecarboxylic acidand shellac flakes are mixed. The resulting mixture is heated until itmelts and flows, typically at about 125 to 135° C. The mixture is thenextruded or poured as a sheet and cooled rapidly to give a solid whereinthe quinolone- or naphthyridonecarboxylic acid is dispersed or dissolvedin the solid matrix of the shellac. The solid is then reduced in size bymeans of a mill to give particles between 20 to 100 mesh sizes dependingon the intended use.

[0014] Where excipients, carriers or auxiliaries are required, theparticles can be mixed with a suitable excipient to give an end product.Alternately, the excipients, carriers or auxiliaries can be chargedinitially in a conventional mixer and mixed. To this mixture, thequinolone- or naphthyridonecarboxylic acid embedded in the insolublematrix is added. The thus-obtained mixture is then admixed using mixersincluding high intensity mixers having chopping devices. The ratio ofquinolone- or naphthyridonecarboxylic acid to the insoluble matrix inthe solid dispersion prepared according to this invention is about 1:0.5to 10, preferably 1:2 to 8, more preferably 1:5.

[0015] As set forth above, solid dispersion can be extruded orpelletized or in powdered form. The formulations according to theinvention can be applied dry on food pellets. One can employ therewithsuitable binders, for example, vegetable, animal or synthetic oils,fats, fatty acids, fatty alcohols, waxes and gelatine. The formulationsprepared according to the invention can, inter alia, also be filled intocapsules, the capsule wall being made of hard or soft gelatin. Thecapsule can, if appropriate, be enteric-coated.

[0016] The formulations prepared by the process according to theinvention can be used as such or in a formulation adapted to theprophylaxis or therapy of diseases in humans or target animals, inparticular the treatment of bacterial infections. They are especiallysuitable for use in the fields of geriatrics and pediatrics or inveterinary practice in taste-sensitive animals, such as, for example,cats and pigs. In effect, the invention provides a process for improvinganimal “uptake” of the quinolone- or naphthyridonecarboxylic acid byanimals, by providing it in a solid dispersion of an insoluble matrix,such as shellac.

[0017] The dispersions and formulations thereof are active againstmicrcorganisms pathogenic to humans and animals. These microorganismsinclude:

[0018] 1. Spirochaetaceae (for example, Treponema, Leptospira andBorrelia)

[0019] 2. Spirillaceae

[0020] 3. Micrococcaceae (for example, staphylococci of biotype A-F andSt. hyicus)

[0021] 4. Streptococcacease (for example, Streptococcus uberis. Str.Equi. Str. agalactiae, Str. dysgalactiae and streptococci of theLancefield groups A-N)

[0022] 5. Pseudomonaceae (for example, Pseudomonas malei, Ps. cepacia,Ps. aeruginosa, Ps. maltophilia), Brucella, such as Brucella abort, B.melitensis, B. suis and Bordetella, such as Bordetella bronchiseptica,Moraxella, Acinetobacter)

[0023] 6. Enterobacteriaceae (for example, Salmonella of the types B-E,Shigella, E. coli, Klebsiella, Proteus, Citrobacter, Edwardsiella,Haemophilus, Providencia and Yersina)

[0024] 7. Vibronaceae (for example, Bribrio such as Vibrio chloerae),Pasteurella such as Pasteurella multocia, Aeromonas, Actinobacillus andStreptobacillus)

[0025] 8. Bacteroidaceae (for example, Bacteroides, Fusobacterium)

[0026] 9. Erysiphylothix and Listeria such as Listeria monocytojenes

[0027] 10. Bacillaceae (for example, Bacillus, Closteridium types A-D,such as Clostridium perfringens), Lactobacillaceae and also anaerobiccocci such as, for example, Peptostreptococci and Peptococci

[0028] 11. Coryneform bacteria (for example, Corynebacterium pyogenes)

[0029] 12. Mycobacteriaceae (for example, Mycobacterium bovis, M. avium,and M. tuberculosis)

[0030] 13. Actinomyceae (for example, Actinomyces bovis and A. israelii)

[0031] 14. Nocardiaceae (for example, Norcardia facinica and N.asteroides)

[0032] 15. Rickettsjaceae (for example, Coxiella and Rickettsia)

[0033] 16. Bartonellaceae (for example, Baronella)

[0034] 17. Chlamydiaceae (for example, Chlamydia psittaci)

[0035] 18. Mycoplasmataceae (for example, Mycoplasma mycoides, M.agalactiae and M. gallisepticum)

[0036] Microorganisms pathogenic to humans and animals can cause diseasesymptoms in mono- or mixed infections of the following animal organsystems: lungs and intratracheal lumen, digestive systems such asstomach and intestine, breast and udder, genital system such as uterus,soft tissue such as skin, muscles, nails, claws, hoofs, active andpassive locomotive system such as bones, muscles, sinews, joints andurogenital system such as kidney, urethra, ureter, nervous system, ears,eyes and gills.

[0037] As already mentioned, the formulations are used to fightbacterial diseases in humans and animals. The animals include: mammals,such as, for example, cattle, horses, pigs, sheep, goats, dogs, cats,camels, animals such as mink, chinchilla, zoo animals and laboratoryanimals such as, for example, mice and rats; birds, such as, forexamples, geese, chickens, turkeys, ducks, pigeons, aviary birds,laboratory birds, such as, for example, parrots and budgerigars;reptiles, such as, for example, crocodiles, snakes, frogs; crustaceans,such as, for example, Penaeidae; for example P. monodon, crabs,lobsters.

[0038] The bacterial diseases of animals include: swine dysentery,spirochactosis in fowl, leptospirosis in cattle, swine, horses, dogs:Campylobacter-induced enteritis in cattle; Campylobacter-inducedabortion in sheep and swine; Campylobacter-induced hepatitis in chicken,infections of the skin; pyoderma in dogs, otitis externa; mastitis incattle, sheep and goats; streptococcal mastitas, streptococcalinfections of the horse, of pigs and other kinds of animals;pneumococcal infections of the calf, and of other kinds of animals;glanders; conjunctivitis; enteritis; pneumonia; brucellosis in cattle,sheep, swine; stropic rhinitis of swine; salmonellosis in cattle,horses, sheep, chicken and other kinds of animals; septicemia;Escherichia coli infections in piglets;metritis-mastitis-agalactic-(MMA)-syndrome; Klebsiella infections;pseudotuberculosis; contagious pleuropneumonia; primary pasteurelloses;foal ataxia; necrobacilllosis in cattle and pets; leptospirosis;erysipelas of swine and other kinds of animals; listeriosis; anthrax;clostridioses; tetanus infections; botulism; infections withCorynebacterium pyogenes; tuberculosis in cattle, swine, fowl and otherkinds of animals; paratuberculosis of the ruminants; nocardiosis; Qfever; ornithosis-psittacosis; encephalomycelitis; mycoplasmosis ofcattle and other animals and porcine enzootic pneumonia.

[0039] The invention is further described by the following illustrativebut non-limiting examples.

EXAMPLES Example 1

[0040] 1. Mix 10 parts micronized enrofloxacin and 90 parts shellac(orange R49) flakes.

[0041] 2. Pulverize in a cone mill, or comminuting mill to reduceparticle size to 100 USP mesh.

[0042] 3. Put in a steel pan heated on an oil bath, or with a heatingmantle, or preferably run through an extruder.

[0043] 4. Heat the mass to 125-134° C. with mixing until a homogeneousmelt is obtained.

[0044] 5. Cool to room temperature and pulverized to pass through adesired mesh size (20-100 USP).

[0045] 6. Mix with suitable excipients to give the end product(medicated feed, oral suspension, or paste.

Example 2

[0046] 1. Mix 10 parts enrofloxacin, 80 parts shellac flakes or powder,and 10 parts sorbitol.

[0047] 2. Pulverize in a cone mill, or comminuting mill to reduceparticle size to 100 USP mesh.

[0048] 3. Put in a steel pan heated on an oil bath, or with a heatingmantle, or preferably run through an extruder.

[0049] 4. Heat the mass to 125-134° C. with mixing until a homogeneousmelt is obtained.

[0050] 5. Cool to room temperature and pulverized to pass through adesired mesh size (20-100 USP).

[0051] 6. Mix with suitable excipients to give the end product(medicated feed, oral suspension, or paste.

Example 3

[0052] 1. Mix 12.5 parts enrofloxacin, 36.1 parts sodium chloride, and51.4 shellac flakes or powder.

[0053] 2. Pulverize in a cone mill, or comminuting mill to reduceparticle size to 100 USP mesh.

[0054] 3. Put in a steel pan heated on an oil bath, or with a heatingmantle, or preferably run through an extruder.

[0055] 4. Heat the mass to 125-134° C. with mixing until a homogeneousmelt is obtained.

[0056] 5. Cool to room temperature and pulverized to pass through adesired mesh size (20-100 USP).

[0057] 6. Mix with suitable excipients to give the end product(medicated feed, oral suspension, or paste.

Example 4

[0058] 1. Mix 20 parts enrofloxacin, 10 parts carbowax 8000, and 70parts shellac flakes or powder.

[0059] 2. Pulverize in a cone mill, or comminuting mill to reduceparticle size to 100 USP mesh.

[0060] 3. Put in a steel pan heated on an oil bath or with a heatingmantle, or preferably run through an extruder.

[0061] 4. Start mixing and heating to 50° C., add 24 parts of water.

[0062] 5. Heat the mass to 125-134° C. with mixing, until a homogeneousmelt is obtained.

[0063] 6. Cool to room temperature and pulverized to pass through adesired mesh size (20-100 USP).

[0064] 7. Mix with suitable excipients to give the end product(medicated feed, oral suspensions, or paste).

[0065] Although the invention has been described in detail in theforegoing for the purpose of illustration, it is to be understood thatsuch detail is solely for that purpose and that variations can be madetherein by those skilled in the art without departing from the spiritand scope of the invention except as it may be limited by the claims.

What is claimed is:
 1. A solid phase dispersion comprising a quinolone-or naphthyridonecarboxylic acid in an insoluble matrix.
 2. Thedispersion according to claim 1, wherein the insoluble matrix isselected from the group consisting of shellac, high molecular weightpolyethylene glycol polyvinyl alcohol, poly(D.L.-lactic co glycolic andsugars.
 3. The dispersion according to claim 2, wherein the insolublematrix is shellac.
 4. The dispersion of claim 1, wherein quinolone- ornaphthyridonecarboxylic acid and the insoluble matrix are in a ratio of1:0.5 to
 10. 5. The dispersion of claim 4, wherein quinolone- ornaphthyridonecarboxylic acid and the insoluble matrix are in a ratio of1:5.
 6. A method of preparing a solid dispersion of a quinolone- ornaphthyridonecarboxylic acid, comprising forming a hydrate of thequinolone- or naphthyridonecarboxylic acid, mixing quinolone- ornaphthyridonecarboxylic acid with an insoluble matrix, heating themixture until it flows, and micronizing the mixture.
 7. A feedformulation comprising feedstuff and the solid phase dispersion ofclaim
 1. 8. A process for improving animal uptake of quinolone- ornaphthyridonecarboxylic acid comprising orally administering to theanimal a solid phase dispersion of a quinolone- ornaphthyridonecarboxylic acid and an insoluble matrix in an effectiveamount to mask the taste of the active.